This invention relates to newly identified polynucleotides, polypeptides encoded by them and to the use of such polynucleotides and polypeptides, and to their production. More particularly, the polynucleotides and polypeptides of the present invention relate to a new member of an ELL family of RNA polymerase II elongation factors, hereinafter referred to as ELL2. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides.
The elongation stage of eukaryotic messenger RNA synthesis is a major site for the regulation of gene expression (Reines, D. et al., Trends. Biochem. Sci. 21:351-355 (1996), Bentley, D. L., Curr. Opin. Genet. Dev. 5:210-216 (1995)). Moreover, a growing body of evidence suggests that mis-regulation of elongation may be a key element in a variety of human diseases (Aso, T. et al., J. Clin. Invest. 97:1561-1569 (1996)).
To date, one virally encoded protein (Tat) and five cellular proteins (SII, P-TEFb, TFIIF, Elongin (SIII), and ELL) have been defined biochemically and shown to be capable of controlling the activity of the RNA polymerase II elongation complex. Among these elongation factors, three have been implicated in human disease. The HIV-1 encoded Tat protein is required for efficient transcription of HIV-1 genes and for productive infection by the virus (Jones, K. A. and Peterlin, B. M., Annu. Rev. Biochem. 63:717-743 (1994)). Elongin (SIII) is a potential target for regulation by the product of the von Hippel-Lindau (VHL) tumor suppressor gene, which is mutated in the majority of clear-cell renal carcinomas and in families with VHL disease, a rare genetic disorder that predisposes individuals to a variety of cancers (Duan, D. R. et al., Science 269:1402-1406 (1995), Kibel, A. et al., Science 269:1444-1446 (1995)). The ELL gene on chromosome 19pl3.1 was originally isolated as a gene that undergoes frequent translocations with the Drosophila trithorax-like MLL gene on chromosome 11q23 in acute myeloid leukemia (Thirman, M. J. et al., Proc. Natl. Acad. Sci. U.S.A. 91:12110-12114 (1994), Mitani, K. et al., Blood 85:2017-2024 (1995)).
This indicates that these proteins have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further related proteins which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, AIDS and neoplastic disorders, among others.
In one aspect, the invention relates to ELL2 polypeptides and recombinant materials and methods for their production. Another aspect of the invention relates to methods for using such ELL2 polypeptides and polynucleotides. Such uses includes the treatment of neoplastic disorders, among others. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with ELL2 imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for the detection of diseases associated with inappropriate ELL2 activity or levels and mutations in ELL2 that might lead to neoplastic disorders (particularly leukemias).